Liraglutide

Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss

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Methods

We used a random sample of 16 million patients (2006-2020) from the PharMetrics Plus for Academics database (IQVIA), a large health claims database that captures 93% of all outpatient prescriptions and physician diagnoses in the US through the International Classification of Diseases, Ninth Revision (ICD-9) or ICD-10. In our cohort study, we included new users of semaglutide or liraglutide, 2 main GLP-1 agonists, and the active comparator bupropion-naltrexone, a weight loss agent unrelated to GLP-1 agonists. Because semaglutide was marketed for weight loss after the study period (2021), we ensured all GLP-1 agonist and bupropion-naltrexone users had an obesity code in the 90 days prior or up to 30 days after cohort entry, excluding those with a diabetes or antidiabetic drug code.

Patients were observed from first prescription of a study drug to first mutually exclusive incidence (defined as first ICD-9 or ICD-10 code) of biliary disease (including cholecystitis, cholelithiasis, and choledocholithiasis), pancreatitis (including gallstone pancreatitis), bowel obstruction, or gastroparesis (defined as use of a code or a promotility agent). They were followed up to the end of the study period (June 2020) or censored during a switch. Hazard ratios (HRs) from a Cox model were adjusted for age, sex, alcohol use, smoking, hyperlipidemia, abdominal surgery in the previous 30 days, and geographic location, which were identified as common cause variables or risk factors.6 Two sensitivity analyses were undertaken, one excluding hyperlipidemia (because more semaglutide users had hyperlipidemia) and another including patients without diabetes regardless of having an obesity code. Due to absence of data on body mass index (BMI), the E-value was used to examine how strong unmeasured confounding would need to be to negate observed results, with E-value HRs of at least 2 indicating BMI is unlikely to change study results. Statistical significance was defined as 2-sided 95% CI that did not cross 1. Analyses were performed using SAS version 9.4. Ethics approval was obtained by the University of British Columbia’s clinical research ethics board with a waiver of informed consent.

Results

Our cohort included 4144 liraglutide, 613 semaglutide, and 654 bupropion-naltrexone users. Incidence rates for the 4 outcomes were elevated among GLP-1 agonists compared with bupropion-naltrexone users (Table 1). For example, incidence of biliary disease (per 1000 person-years) was 11.7 for semaglutide, 18.6 for liraglutide, and 12.6 for bupropion-naltrexone and 4.6, 7.9, and 1.0, respectively, for pancreatitis.

Use of GLP-1 agonists compared with bupropion-naltrexone was associated with increased risk of pancreatitis (adjusted HR, 9.09 [95% CI, 1.25-66.00]), bowel obstruction (HR, 4.22 [95% CI, 1.02-17.40]), and gastroparesis (HR, 3.67 [95% CI, 1.15-11.90) but not biliary disease (HR, 1.50 [95% CI, 0.89-2.53]). Exclusion of hyperlipidemia from the analysis did not change the results (Table 2). Inclusion of GLP-1 agonists regardless of history of obesity reduced HRs and narrowed CIs but did not change the significance of the results (Table 2). E-value HRs did not suggest potential confounding by BMI.

Discussion

This study found that use of GLP-1 agonists for weight loss compared with use of bupropion-naltrexone was associated with increased risk of pancreatitis, gastroparesis, and bowel obstruction but not biliary disease.

Given the wide use of these drugs, these adverse events, although rare, must be considered by patients who are contemplating using the drugs for weight loss because the risk-benefit calculus for this group might differ from that of those who use them for diabetes. Limitations include that although all GLP-1 agonist users had a record for obesity without diabetes, whether GLP-1 agonists were all used for weight loss is uncertain.

A Diabetes Drug Has ‘Significantly Reversed Memory Loss’ in Mice With Alzheimer’s

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A drug developed for type 2 diabetes has “significantly reversed memory loss” in mice with Alzheimer’s disease, and researchers now want to test it on humans.

The treatment is exciting for scientists because it works by protecting the brain cells attacked by Alzheimer’s disease in three separate ways, rather than relying on a single approach.

 

And seeing as the drug has already been tested and approved for use in humans, it’s something that could hit the market a lot faster than other experimental treatment options.

The results have only been seen in mice so far, but the drug “holds clear promise of being developed into a new treatment for chronic neurodegenerative disorders such as Alzheimer’s disease,” said senior author Christian Hölscher of Lancaster University in the UK.

“With no new treatments in nearly 15 years, we need to find new ways of tackling Alzheimer’s,” said Doug Brown from UK organisation, Alzheimer’s Society.

“It’s imperative that we explore whether drugs developed to treat other conditions can benefit people with Alzheimer’s and other forms of dementia. This approach to research could make it much quicker to get promising new drugs to the people who need them.”

Previous research had already established a link between type 2 diabetes and Alzheimer’s – type 2 diabetes is a risk factor for Alzheimer’s, and it also appears to make the disease progress more rapidly.

This could be a result of insulin not getting to the cells properly – insulin is a growth factor which is known to protect brain cells, and insulin resistance has been observed in Alzheimer’s disease brains, as well as being the biological mechanism behind type 2 diabetes.

 So researchers have been investigating whether drugs that treat type 2 diabetes might also benefit Alzheimer’s symptoms for a while now.

They’ve seen previous success in humans with an older diabetes drug known as liraglutide. But this is the first ‘triple agonist’ drug that’s been tested.

The drug, which is referred to only as ‘triple receptor agonist’, or TA, in the paper, acts in multiple ways to protect the brain from degeneration, by activating GIP-1, GIP, and glucagon receptors at the same time.

Seeing as growth factor signalling has been shown to be impaired in the brains of Alzheimer’s patients, the idea was that the drug might help re-stimulate damaged brain cells and protect against further damage.

The researchers tested the drug in mice that had been genetically engineered to have Alzheimer’s disease.

They used a maze to measure the animal’s learning and memory formation, and found that the drug “significantly reversed the memory deficit,” the researchers write.

The drug also:

  • enhanced levels of a brain growth factor which protects nerve cell functioning
  • reduced the amount of toxic amyloid plaques in the brain
  • reduced both chronic inflammation and oxidative stress
  • slowed down the rate of nerve cell loss

“These very promising outcomes demonstrate the efficacy of these novel multiple receptor drugs that originally were developed to treat type 2 diabetes but have shown consistent neuro- protective effects in several studies,” said Hölscher.

There’s still a long way to go before it’s clear whether or not this drug will have the same effect in humans, and whether it’s the best option to move forward with.

“Further dose-response tests and direct comparisons with other drugs have to be conducted in order to evaluate if this new [drug] is superior to previous ones,” Hölscher added.

But the fact that this multi-approach drug has shown such promising results so far is incredibly exciting, and is a great way to start 2018.

After all, more than 5 million Americans are already living with Alzheimer’s, and by 2050 that number could be as high as 16 million. So we definitely need new treatment options.

ADA guidelines embrace heart health

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EXPERT ANALYSIS FROM DIABETES CARE

Recent studies that confirm the cardiovascular benefit of some antihyperglycemic agents are shaping the newest therapeutic recommendations for patients with diabetes and comorbid atherosclerotic cardiovascular disease (ASCVD).

Treatment for these patients – as all with diabetes – should start with lifestyle modifications and metformin. But in its new position statement, the American Diabetes Association now recommends that clinicians consider adding agents proved to reduce major cardiovascular events and cardiovascular death – such as the sodium glucose cotransporter-2 (SGLT2) inhibitor empagliflozin or the glucagon-like peptide 1 (GLP-1) agonist liraglutide – to the regimens of patients with diabetes and ASCVD (Diabetes Care 2018;41(Suppl. 1):S86-S104. doi: 10.2337/dc18-S009).

The medications are indicated if, after being treated with lifestyle and metformin therapy, the patient isn’t meeting hemoglobin A1c goals, said Rita R. Kalyani, MD, who led the ADA’s 12-member writing committee. But clinicians may also consider adding these agents for cardiovascular benefit alone, even when glucose control is adequate on a regimen of lifestyle modification and metformin, with dose adjustments as appropriate, she said in an interview.

“A1c remains the main target of sequencing antihyperglycemic therapies, if it’s not reached after 3 months,” said Dr. Kalyani of Johns Hopkins University, Baltimore. “But, it could also be that the provider, after consulting with the patient, feels it’s appropriate to add one of these agents solely for cardioprotective benefit in patients with ASCVD.”

The recommendation to incorporate agents with cardiovascular benefit is related directly to data from two trials, LEADER and EMPA-REG, which support this recommendation. All of these cardiovascular outcome trials included a majority of patients who were already on metformin. “We developed these evidence-based recommendations based on these trials and to appropriately reflect the populations studied,” said Dr. Kalyani.

The ADA’s “Standards of Medical Care in Diabetes 2018” is the first position statement from any professional society to provide specific recommendations for the incorporation of these newer antihyperglycemic agents for their cardioprotective benefit, as well as their ability to lower blood glucose effectively. But the document provides much more than an algorithm for treating patients with concomitant ASCVD, Dr. Kalyani said. It is a comprehensive clinical guide covering recommendations for diagnosis, medical evaluation, comorbidities, lifestyle change, cardiovascular risk management, and treating diabetes in children and teens, pregnant women, and patients with hypertension.

The 2018 update contains a number of new recommendations; more will be added as new data emerge, since the ADA intends it to be a continuously refreshed “living document.” This makes it especially clinically useful,Paul S. Jellinger, MD, said in an interview. A member of the writing committee of the American Association of Clinical Endocrinologists’ diabetes management guidelines, Dr. Jellinger feels ADA’s previous versions have not been as targeted as this new one and, he hopes, its subsequent iterations.

Dr. Paul S. Jellinger professor of clinical medicine at the University of Miami

Dr. Paul S. Jellinger

“This is a nice enhancement of previously published guidelines for diabetes therapy,” said Dr. Jellinger, professor of clinical medicine at the University of Miami. “For the first time, ADA is providing some guidance in terms of which agents to use. It’s definitely more prescriptive than it was in the past, when, unlike the AACE Diabetes Guidelines, it was a palette of choice for clinicians, but with very little guidance about which agent to pick. The guidance for patients with cardiovascular disease in particular is big news because these antihyperglycemic agents showed such a significant cardiovascular benefit in the trials.”

While the document gives a detailed algorithm of advancing therapy in patients with ASCVD, it doesn’t specify a preference for a specific drug class after metformin therapy in patients without ASCVD. Instead, it provides a detailed table listing the drug-specific effects and patient factors to consider when selecting from different classes of antihyperglycemic agents ( SGLT2 inhibitors, GLP-1 agonists, DPP-4 inhibitors, thiazolidinones, sulfonylureas, and insulins). The table notes the drugs’ general efficacy in diabetes, and their impact on hypoglycemia, weight gain, and cardiovascular and renal health. The table also includes the Food and Drug Administration black box warnings that are on some of these medications.

Another helpful feature is a cost comparison of antidiabetic agents, Dr. Kalyani noted. “Last year we added comprehensive cost tables for all the different insulins and noninsulins, and this year we added a second data set of cost information, to assist the provider when prescribing these agents.”

The pricing information is a very important addition to this guideline, and one that clinicians will appreciate, said Richard Hellman, MD, clinical professor of medicine at the University of Missouri–Kansas City.

“In this document, ADA is urging providers of care to ask about whether the cost of their diabetes care is more than they can deal with. They present tables which compare the costs of the current blood glucose lowering agents used in the U.S., and it is plain to see that many patients, without insurance coverage, will find some of the medications unaffordable,” said Dr. Hellman, a past president of AACE. “They also provide data that show half of all patients with diabetes have financial problems,” and he suspects that medication costs are an important component of their financial insecurity.

Dr. Richard Hellman, clinical professor of medicine at the University of Missouri-Kansas City and associate program director of the UMKC Endocrine Fellowship

Dr. Richard Hellman

The document also notes data from the 2017 National Health and Nutrition Examination Survey, which found that 10% of people with diabetes have severe food insecurity and 20% have mild food insecurity (Diabetes Educ. 2017;43:260-71. doi: 10.1177/0145721717699890).

“Another thing the document points out is that two-thirds of the patients who don’t take all their medications due to cost don’t tell their doctor,” Dr. Hellman said. “The ADA is making the point that providers have a responsibility to ask if a patient is not taking certain medications because of the cost. We have so many better tools to manage this disease, but so many of these tools are unaffordable.”

While the treatment algorithm for patients with ASCVD will likely be embraced, another new recommendation may stir the pot a bit, Dr. Hellman noted. The section on cardiovascular disease and risk management goes out on its own, sticking to a definition of hypertension as 140/90 mm Hg or higher – a striking diversion from the new 130/80 mm Hg limit set this fall by both the American Heart Association and the American College of Cardiology.

“This difference in recommendations is very important and will be controversial,” Dr. Hellman said, adding that he agrees with this clinical point.

Again, this recommendation is grounded in clinical trials, which suggest that people with diabetes don’t benefit from overly strict blood pressure control. The new AHA/ACC recommendations largely drew on data from the SPRINTtrial, which was conducted in an entirely nondiabetic population. “These gave a clear signal that a lower BP target is beneficial to that group,” Dr. Hellman said.

But large well-designed randomized controlled trials of intensive blood pressure lowering in people with diabetes, such as ACCORD-BP, did not demonstrate that intensive blood-pressure lowering targeting a systolic less than120 mm Hg had a significant benefit on the composite primary cardiovascular endpoint. And while the ADVANCE BP trial found that the composite endpoint was improved with intensive blood pressure lowering, the blood pressure level achieved in the intervention group was 136/73 mm Hg.

“This recommendation is based on current evidence for people with diabetes,” Dr. Kalyani said. “We maintain our definition of hypertension as 140/90 mm Hg or higher on the results of large clinical trials specifically in people with diabetes but emphasize that intensification of antihypertensive therapy to target lower blood pressures (less than 130/80 mm Hg) may be beneficial for high-risk patients with diabetes such as those with cardiovascular disease. We are constantly assessing the evidence and will continue to review the results of new studies for potential incorporation into recommendations in the future.”

Liraglutide, metformin combination reduces risk for diabetes in postpartum women

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The addition of liraglutide to metformin led to greater weight loss and improvements in insulin secretion and action in women who were overweight, obese and had a history of gestational diabetes when compared with metformin alone, according to study results presented at the American Diabetes Association Scientific Sessions.

The combination therapy was also more effective in reducing triglyceride to HDL-cholesterol ratio and mean blood glucose levels compared with metformin monotherapy, according to the researchers.

Karen Elkind-Hirsch

Karen Elkind-Hirsch

“We knew that getting the weight off [in this patient population] was critical,”Karen Elkind-Hirsch, PhD, MSc, HCLD, scientific director of research at Woman’s Hospital in Baton Rouge, Louisiana, told Endocrine Today. “That was the impetus about perhaps using a glucagon-like peptide 1 receptor agonist, because we know a side effect is weight loss.”

Initiating weight loss is important, Elkind-Hirsch said, because gestational diabetes mellitus (GDM) is associated with maternal obesity, and obesity and weight gain are associated with an increased risk for type 2 diabetes.

Elkind-Hirsch and colleagues randomized 110 overweight women (BMI > 25 kg/m2) aged 18 to 45 years who experienced GDM within 12 months of pregnancy to either 2000 mg of metformin and 1.8 mg of subcutaneous liraglutide (Victoza, Novo Nordisk) or metformin at 2000 mg and placebo for 36 weeks.

Seventy-six women completed the 32 to 36-week follow-up visit. The results demonstrated that the combination therapy was more effective in reducing BMI (P = .018), triglyceride to HDL-cholesterol ratio (P < .03) and mean blood glucose levels (P < .03).

The researchers noted that impaired glucose regulation was identified in 15 patients on combination therapy and 9 patients who received metformin monotherapy.

Twelve patients who received the combination therapy and four patients who received metformin and placebo returned to normoglycemia (P < .025). The remaining 23 patients who received dual therapy showed improved or no significant change.

Elkind-Hirsch acknowledged that there are two more intervals that need to be tested before the study is completed.

“The reason that we did that was in the New England Journal of Medicine, there was a wonderful paper many years ago that looked at women with gestational diabetes and [the researchers] said ideally mothers should put 2 years between their children for the safety of their pancreas to recover,” she said. “I chose that they’re getting into the trial 3 or 4 months out and then I’m following them for 18 months and hopefully they’re healthier by the time that they get off the medications.” – by Ryan McDonald

‘New Era’ of Type 2 Diabetes Treatment as LEADER Unveiled?

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Details of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER) trial of the glucose-lowering drug liraglutide (Victoza, Novo Nordisk), showing that it significantly reduced the rates of major adverse cardiovascular events in type 2 diabetes patients at elevated cardiovascular risk, were reported today.

The study is the second such mandated FDA cardiovascular safety study for a diabetes drug to show cardiovascular benefit, rather than just lack of harm, on top of standard therapy in type 2 diabetes patients at high cardiovascular risk after the EMPA-REG trial, and the first with an agent from the glucagonlike peptide 1 (GLP-1) receptor agonist class. Results of a previous trial with another GLP-1 agonist, ELIXA, were neutral.

Experts here said that LEADER and EMPA-REG may now begin to change the landscape of diabetes therapy, giving doctors a somewhat clearer choice when deciding which drug to use second line after metformin in type 2 diabetes.

The results from the multicenter, international study were presented June 13, 2016 here at the American Diabetes Association (ADA) 2016 Scientific Sessions and were published online simultaneously in the New England Journal of Medicine, by Steven P Marso, MD, of University of Texas Southwestern Medical Center, Dallas, and colleagues.

LEADER began in 2010 and followed 9340 high-risk adults with type 2 diabetes for 3.5 to 5 years, who were randomly assigned to receive either a subcutaneous injection of liraglutide 1.8 mg once daily (or the maximum tolerated dose) or placebo along with standard treatment.

The primary end point was the first occurrence of the three-point major adverse cardiac event (MACE) components: cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke.

The degree of risk reduction for MACE was 13% (occurring in 608 of 4668 patients taking liraglutide) vs 14.9% (in 694 of 4672 taking placebo) (P = .01 for superiority), including a 22% lower rate of cardiovascular death (4.7 vs 6.0%, P = .007), Dr Marso reported in a press briefing held at the ADA meeting in advance of a special 2-hour symposium devoted to the findings.

The number of patients who would be needed to treat to prevent one event in 3 years was 66 for the MACE composite and 98 for death from any cause.

Liraglutide also reduced HbA1c, body weight, and hypoglycemia, and its safety profile was similar to what has been seen in previous trials, with gastrointestinal adverse events and increases in heart rate being the most common.

New Trials Inform Clinical Choice of Second Drug for Type 2 Diabetes

Coming on the heels of the cardiovascular benefit seen for the sodium glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) in the EMPA-REG trial, the LEADER findings have experts talking about a “new era” in the management of type 2 diabetes.
While most agree that metformin remains the first-line drug of choice, these new landmark study data are starting to better inform the clinical choice of second drug based on characteristics beyond their glucose-lowering capacity, speakers said during the press briefing.

“In type 2 diabetes, most of us agree that under most circumstances metformin is the drug of choice,” briefing moderator Robert H Eckel, MD, of the University of Colorado, Denver, said, noting that additional potential cardiovascular and also anticancer benefits have been seen with that drug as well.

However, he said, “It’s interesting, with LEADER the benefit for cardiovascular death is very similar to what statins do. I think with validation, it could potentially change practice….I’d like to see second and third trials for both [liraglutide and empagliflozin]. Keep in mind there are 25 or 30 trials for statins showing benefit,” said Dr Eckel, who was not involved in LEADER or EMPA-REG.

Senior investigator of LEADER, John Buse, MD, of the University of North Carolina, Chapel Hill, added: “I think this changes the conversation with patients. Now, instead of just saying we’re giving you this drug to manage your hyperglycemia in diabetes, [we can say] this drug also has the potential to modify your risk for cardiovascular disease and death.

“It was beyond our expectations that we would be able to demonstrate cardiovascular efficacy,” he told the press briefing.

Asked to comment, Simon Heller, MD, professor of clinical diabetes, University of Sheffield, United Kingdom, toldMedscape Medical News, “I think we are in a different era now. People die from hypoglycemia, whether by insulin or sulfonylureas. We shouldn’t forget that.

“These drugs [liraglutide and empagliflozin] don’t cause hypoglycemia and have other effects that may be beneficial. I agree absolutely we need to confirm with other studies, but I think we’re definitely going to see a shift toward modern therapies.”

Benefits Seen for Multiple Cardiovascular End Points

The LEADER trial included patients with type 2 diabetes who had HbA1c levels of 7.0% or higher. Entry criteria were either age 50 and above with established cardiovascular disease or chronic renal failure or age 60 and older with CVD risk factors.
Dr Robert H Eckel on podium; left to right, Drs Simon Heller, John Buse, Steven P Marso, and Bernard Zinman

Patients could be drug-naive or taking oral agents or basal insulin but not other GLP-1 agonists or DPP-4 inhibitors, pramlintide, or rapid-acting insulin. In both treatment and placebo groups, current standards of care were targeted for HbA1c, blood pressure, lipids, and antiplatelet therapy.

Subjects had a mean baseline age of 64 years, diabetes duration 13 years, and HbA1c 8.7%.

At 36 months’ postrandomization, HbA1c levels were 0.40 percentage points lower in the liraglutide group, a significant difference (P < .001). Body weight also dropped significantly, by 2.3 kg (P < .001).

Overall, results for each of the components of the composite primary MACE outcome were in favor of liraglutide, with a 22% reduction in cardiovascular death (4.7% vs 6.0%, P = .007), which was significant, and a nonsignificant 12% reduction in nonfatal MI (6.0% vs 6.8%, P = .11) and an 11% lower rate of nonfatal stroke (3.4% vs 3.8%, P = .30).

Also significant were a 15% reduction in all-cause death (8.2% vs 9.6%, P = .02) and an expanded composite CV outcome that included coronary revascularization, unstable angina, or hospitalization for heart failure (20.3% vs 22.7%, P = .005).

Hospitalization for heart failure itself was 13% less frequent in the liraglutide group (4.7% vs 5.3%, P = .14). Although not statistically significant in terms of benefit, the lack of any signal for concern with regard to heart failure is noteworthy, Dr Marso said. “There has been a lot of discussion in the incretin space about whether agents such as SGLT2 inhibitors, DPP-4 inhibitors, or GLP-1 receptor agonists are neutral, hazardous, or beneficial for heart failure.”

He added: “What’s striking is the consistency in the relative risk reduction in all of the major cardiovascular end points that we measured in LEADER.”

The prespecified primary microvascular outcome in LEADER was a composite of nephropathy and retinopathy outcomes, and there was a benefit with liraglutide over placebo: time to first renal event was 22% longer with liraglutide, a significant difference. However, this latter effect drove the benefit, as there was no significant difference in retinopathy events between the two groups.

Safety Profile Shows No Signals

Overall adverse events occurred in two-thirds of both treatment groups and were not significantly different (P = .12). Serious adverse events occurred in 50% of both groups and severe events in a third of both (P = .51).

Adjudicated cases of acute pancreatitis occurred in 0.4% of patients taking liraglutide compared with 0.5% on placebo (P = .44). There were two cases of chronic pancreatitis, both in the placebo group.

However, acute gallstone disease was more common with liraglutide, 3.1% vs 1.9% (P < .001).

Hypoglycemia was more common in the placebo group, both with overall confirmed cases of blood glucose levels below 56 mg/dL (43.7% with liraglutide vs 45.6% with placebo, P < .001) and in severe hypoglycemia requiring assistance (2.4% vs 3.3%, P = .016). The likely reason for this, Dr Eckel noted, is that the placebo patients may have been treated more intensively with insulin in attempt to achieve HbA1c targets.

Neoplasms were not different between the groups except for a 46% reduction in prostate cancer (0.9% vs 1.6%) and a lower rate of leukemias (0.1% vs 0.3%) in the liraglutide group.

There was a numeric increase in the number of pancreatic-cancer cases with liraglutide (13 vs five) for a higher rate of pancreatic cancer in the liraglutide group (0.3% vs 0.1%), but four more cases were identified on imaging in the placebo group that did not have pathology to establish the diagnosis, so the two groups were not significantly different, Dr Buse noted.

Everything Changing Modestly, but in the Right Direction

Dr Eckel said that the results of LEADER follow in the same vein as those of EMPA-REG.

“In EMPA-REG, many things related to CVD risk were modified in a modest but favorable way. LEADER gives a hint of the same kind of modification.…Everything is kind of changing modestly in the right direction.”

But the LEADER investigators note some differences in how the drugs may be working.

“The pattern of cardiovascular benefits that were associated with liraglutide in our trial appears to differ from that with the SGLT-2 inhibitor empagliflozin in the previously reported EMPA-REG OUTCOME trial.”

The time to benefit emerged earlier in EMPA-REG than in LEADER, they note, and the variability of the direction and magnitude of the effects on the components of the composite primary outcome in that trial “contrasts with the consistency of effect in the present trial.”

The observed benefits in EMPA-REG “may be more closely linked to hemodynamic changes, whereas in the present trial, the observed benefits are perhaps related to the modified progression of atherosclerotic vascular disease,” they conclude.

Liraglutide Doesn’t Lower LVEF in HF but Does Increase Heart Rate, Says LIVE Trial

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A new study agrees with recent research that the glucagonlike peptide-1 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk) has no clinical benefit for patients with heart failure (HF), but it adds to the literature by noting some serious treatment-related CV events.

Last fall, results from the FIGHT trial showed no significant differences in 6-month outcomes, including mortality and rehospitalization, between the antidiabetic drug and placebo in 300 patients with acute HF and reduced ejection fraction (HFrEF). However, as expected, weight decreased and glycemic control improved in the subgroup with diabetes.

The newly reported LIVE trial enrolled 241 patients with chronic HFrEF at five centers in Denmark. After 24 weeks of treatment, there were no significant differences between the liraglutide and placebo groups for the primary end point of change in LVEF—whether the patients did or did not have comorbid diabetes[1].

More troubling, there was a significant increase in heart rate for those receiving liraglutide vs placebo (P<0.001) and more serious adverse cardiac events (12 vs three, respectively, P=0.04).
Dr Henrik Wiggers

Principal investigator Dr Henrik Wiggers (Aarhus University Hospital, Denmark) told heartwire from Medscape that even a moderately elevated resting heart rate can have a negative effect on HF and that that may explain the increased adverse events they found in their study.

“Although I must stress that this was a secondary end point, if a patient like this came to me to discuss getting a GLP-1 analogue, I would hesitate,” added Dr Anders Jorsal (Aarhus University Hospital), who presented the findings during a late-breaking-trial session here at the European Cardiology Society (ESC) Heart Failure 2016 Congress.

Official discussant Michel Komajda (Groupe Hospitalier Pitié-Salpêtrière, Paris, France) called LIVE’s results disappointing and the adverse events worrisome. “At the moment, liraglutide may not be the drug of choice for heart failure and diabetes.”

“We Expected Better”
Dr Anders Jorsal

“We currently don’t know how to treat diabetes in heart failure and so wanted to study whether liraglutide could improve LVEF,” said Jorsal.

He added that some pilot studies and experimental data “have been very promising” for this treatment and have shown LVEF improvements for HF patients with and without type 2 diabetes mellitus, which made them hopeful.

“We really expected better for our patients,” he said.

In the study, 122 of the patients were randomly assigned to liraglutide and 119 to placebo (89% men and mean age 65 years in each group). In addition, 32% and 29% of the groups, respectively, had type 2 diabetes.

Inclusion criteria for this study included LVEF <45% and an NYHA classification of 1–3. All participants underwent 3D contrast echocardiography to measure LVEF changes from baseline, as well as blood-pressure measurements and a 6-minute-walk test, and they filled out the Minnesota Living with Heart Failure (MLHF) questionnaire.

Surprising Results

At 6 months, the liraglutide-receiving group had a 0.8% change in LVEF vs a 1.5% change in the placebo group (P=0.24). “And there were no between-group differences in other measures of systolic function,” reported Jorsal.

Weight loss was significantly greater in the liraglutide vs placebo groups (-2.2 kg vs 0.1 kg, respectively; P<0.001), HbA1c level was significantly reduced (-5.1 mmol/mol vs 3.2 mmol/mol, P<0.001), and the 6-minute-walk test was significantly improved (P=0.04).

However, heart rate was increased by 6 beats per minute in the liraglutide patients vs a decrease of 1 beat in the placebo patients (P<0.001). In addition, there were four vs two reports of atrial fibrillation, respectively, three vs zero reports of ACS, three vs one nonfatal VTs, one vs zero fatal VTs, and one vs zero worsening of heart failure.

“This study wasn’t actually powered to detect any clinical-end-point differences. So we were surprised by this,” said Wiggers. “We now need larger studies to confirm these serious clinical effects.”

He noted that the ongoing, 9000-person strong Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Results (LEADER) trial, which announced top-line results in March, has excited many people in the field. “But only a minority of its patients had heart failure at baseline, and the type of heart failure is probably unknown.” Although it’ll be interesting to see what LEADER shows when its full results are released, “it might not be enough,” he said.

Caution for Now

After the presentation, discussant Komajda said that the clinical implications of both the LIVE and FIGHT trials are that there is no evidence of clinical benefit in cardiac function with liraglutide and that CV safety in diabetes with HF or LV dysfunction “remains an open question.”

Session moderator Dr Frank Ruschitzka (University of Zurich, Switzerland) called diabetes and HF “vicious twins” and noted that the ESC’s Heart Failure Association has just opened a new committee focused on the joint conditions.

He later told heartwire that the LIVE trial was intriguing and shed some light on important topics, “including some important safety signals” for arrhythmic events. “It’s a small study, so I don’t want to overplay these results. But safety should come first.”

Although he’s looking forward to upcoming outcomes studies, Ruschitzka said that at present he would not treat a patient of this type with this kind of drug. And that won’t change “until I see the final analysis [from ongoing large trials] presented and published.”

A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management — NEJM

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Background

Obesity is a chronic disease with serious health consequences, but weight loss is difficult to maintain through lifestyle intervention alone. Liraglutide, a glucagon-like peptide-1 analogue, has been shown to have potential benefit for weight management at a once-daily dose of 3.0 mg, injected subcutaneously.

Methods

We conducted a 56-week, double-blind trial involving 3731 patients who did not have type 2 diabetes and who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of at least 30 or a BMI of at least 27 if they had treated or untreated dyslipidemia or hypertension. We randomly assigned patients in a 2:1 ratio to receive once-daily subcutaneous injections of liraglutide at a dose of 3.0 mg (2487 patients) or placebo (1244 patients); both groups received counseling on lifestyle modification. The coprimary end points were the change in body weight and the proportions of patients losing at least 5% and more than 10% of their initial body weight.

Results

At baseline, the mean (±SD) age of the patients was 45.1±12.0 years, the mean weight was 106.2±21.4 kg, and the mean BMI was 38.3±6.4; a total of 78.5% of the patients were women and 61.2% had prediabetes. At week 56, patients in the liraglutide group had lost a mean of 8.4±7.3 kg of body weight, and those in the placebo group had lost a mean of 2.8±6.5 kg (a difference of −5.6 kg; 95% confidence interval, −6.0 to −5.1; P<0.001, with last-observation-carried-forward imputation). A total of 63.2% of the patients in the liraglutide group as compared with 27.1% in the placebo group lost at least 5% of their body weight (P<0.001), and 33.1% and 10.6%, respectively, lost more than 10% of their body weight (P<0.001). The most frequently reported adverse events with liraglutide were mild or moderate nausea and diarrhea. Serious events occurred in 6.2% of the patients in the liraglutide group and in 5.0% of the patients in the placebo group.

Conclusions

In this study, 3.0 mg of liraglutide, as an adjunct to diet and exercise, was associated with reduced body weight and improved metabolic control.

Once-daily liraglutide may intensify insulin treatment in type 2 diabetes.

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In patients whose type 2 diabetes is not sufficiently controlled by insulin degludec and metformin, the addition of once-daily liraglutide provides better glycemic control and weight-loss benefits than the addition of once-daily insulin aspart, recent study results found.

“Thus, this therapeutic option should be considered when basal insulin therapy requires intensification,” the researchers wrote.

The multinational (119 sites in 12 countries) phase 3b, open-label, randomized, treat-to-target study compared the addition of once-daily liraglutide (Victoza, Novo Nordisk) with the addition of once-daily insulin aspart (NovoLog FlexPen, Novo Nordisk) to an existing regimen of once-daily insulin degludec and metformin. All patients continued taking metformin during the trial, which lasted for 28 days. There were three parallel arms in the study: two were randomized (insulin degludec and liraglutide, n=88; insulin degludec and insulin aspart, n=89) and one was not randomized (insulin degludec and metformin, n=236).

The researchers found that insulin degludec and liraglutide decreased HbA1c significantly more than insulin degludec and insulin aspart (–0.74% vs. –0.39%), with an estimated treatment difference of –0.32% (95% CI, –0.53 to –0.12). More insulin degludec and liraglutide (49.4%) than insulin degludec and insulin aspart (7.2%) patients achieved HbA1c <7% without hypoglycemia or severe hypoglycemia, and without weight gain. Participants in the insulin degludec and liraglutide arm had significantly less confirmed and nocturnal confirmed hypoglycemia, and statistically more weight loss (−2.8 kg) vs. those in the insulin degludec and insulin aspart arm (0.9 kg, P<.0001).

With the exception of more gastrointestinal side effects seen with insulin degludec and liraglutide, there were no differences in safety.

According to the researchers, these findings could represent a valid option for insulin intensification when basal insulin is not sufficient for glycemic control.

Source: Endocrine Today

Liraglutide-metformin combo superior to either treatment alone for weight loss in PCOS.

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Short-term combination liraglutide and metformin yielded significant weight loss among obese women with polycystic ovary syndrome,Mojca Jensterle Sever, MD, PhD, of the University Medical Center in Ljubljana, Slovenia, told Endocrine Today here at ENDO 2013.

“Obesity is a great problem in women with polycystic ovary syndrome (PCOS) and we do not have a conventional satisfactory treatment for it. The most widely used drug is metformin for women with PCOS and metabolic disturbances, but it’s somehow not successful enough to curb obesity. That’s why we tried to use our experience with diabetes to test long-acting GLP-1 agonists for any effect on the PCOS population,” Jenterle Sever said in an interview.

She and colleagues conducted a 12-week open, metformin-controlled trial by randomly assigning 36 obese women with PCOS aged 31.3 years (BMI 37.1 kg/m2) to one of the following treatment arms: metformin 1,000 mg twice daily (n=14), liraglutide (Victoza, Novo Nordisk) 1.2-mg administered daily subcutaneously (n=11) or combined therapy (n=11).

Jensterle Sever said that 38% of patients lost ≥5% body weight (22% in the combination group, 16% in the liraglutide group and zero in the metformin group). Patients assigned to combination therapy lost an average of 6.5 kg vs. 3.8 kg among those in the liraglutide group and 1.2 kg in the metformin group (P<.001), according to data.

Patients in the combination group also demonstrated a greater decrease in BMI and waist circumference compared with the other two treatment groups, according to data.

“We found that this combined arm was more successful in reducing weight, BMI and waist circumference as compared with liraglutide and metformin treatment arm alone.”

Adverse events included nausea during liraglutide treatment. However, this effect gradually declined over time and was not correlated with weight loss, Jensterle Sever said.

These findings suggest that short-term combined treatment of liraglutide and metformin led to statistically significant weight loss in obese women with PCOS. – by Samantha Costa

Source: Endocrine today

Liraglutide may reduce liver enzyme levels in patients with type 2 diabetes.

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Patients with elevated liver enzymes were safely treated with liraglutide, although the treatment’s effect was reduced by its impact on weight and glycemic control, according to recent results.

Researchers performed a meta-analysis of data on 4,442 patients enrolled in six 26-week, phase 3 randomized controlled trials evaluating the impact of liraglutide on liver enzymes in patients with type 2 diabetes. Liraglutide was assigned to 2,734 patients in the cohort, while 524 received placebo and 1,184 received other diabetes treatments.

In all studies, patients initially received 0.6 mg intravenous liraglutide once a day, titrated to 1.2 mg daily after 7 days, with some studies increasing dosage to 1.8 mg after 7 additional days. One study (LEAD-2) randomly assigned patients to receive 0.6 mg, 1.2 mg or 1.8 mg once a day, along with metformin and 4 mg glimepiride or placebo per day. LEAD-2 also included a sub-study assessing the drug’s impact on hepatic steatosis.

Abnormal baseline ALT levels were present in 50.8% of patients. A 1.8 mg dose of liraglutide resulted in a significantly larger ALT reduction than that observed among patients receiving placebo (–8.20 IU/L vs. –5.01 IU/L; P=.003 for difference); no significant differences were observed between placebo and smaller doses of liraglutide. Investigators noted that adjusting for HbA1c (P=.63) and liraglutide’s weight reduction (P=.21) eliminated the statistical significance of the drug’s impact. Rates of adverse events were similar among patients with or without elevated ALT at baseline when treated with 1.2 mg or 1.8 mg liraglutide.

In the LEAD-2 sub-study, the 1.8 mg liraglutide dose trended toward improving steatosis relative to placebo, with a 0.10 improvement to liver-to-spleen attenuation ratio among treated patients compared with 0.0 among those receiving placebo (P=.07). Adjusting for changes to weight (P=.25) and HbA1c (P=.93) reduced this trend.

“[Twenty-six] weeks’ treatment with liraglutide 1.8 mg has an acceptable safety profile and significantly improves liver enzymes vs. placebo in patients with type 2 diabetes and asymptomatic liver injury,” the researchers wrote. “These effects appear to be mediated by the effect of liraglutide on weight loss and glycemic control. Our data support the rationale to prospectively investigate GLP-1 analogues in liver injury associated with type 2 diabetes and the metabolic syndrome.”

  • Source: Endocrine Today.